Prior History Of Thrombosis Research Articles

DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study.

Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.

An Innovative Dynamic Nomogram for Stratifying Survival Prognosis in Essential Thrombocythemia Patients with a History of Thrombosis

Background:Essential thrombocythemia (ET) with a previous history of thrombosis was classified as high risk according to the revised International Prognostic Score for Thrombosis in ET. However, prognostic factors are not well established in this patient population. With the aim of enhancing patient outcomes, we endeavored to develop a prognostic nomogram specifically for patients with ET and a prior history of thrombosis. Methods:We included 318 ET with previous arterial or venous thrombosis or both from January 2008 to June 2022 in our study. We used multivariable Cox proportional hazards regression to build a dynamic prognostic nomogram for this patient population. Harrell C Index was used for nomogram discrimination. Internal validation was performed by bootstrap resampling. The area under the receiver operating characteristic curve (AUC) was used to determine the nomogram's performance. Results:Based on the IPSET model, out of the 318 patients, 148 were categorized as having an intermediate risk (score of 1-2), while 170 patients were classified as high risk (score greater than or equal to 3). Substantial statistical significance was observed in the overall survival between these two groups, underscoring the ability of the IPSET model to stratify prognosis in essential thrombocythemia patients with a history of thrombosis . We further used multivariable cox regression analysis and found that Age≥60 years (HR=5.68 [95% CI:1.44-22.47], p=0.013), splenomegaly (HR=5.66 [95% CI:1.74-18.43], p=0.004), abnormal karyotype (HR=5.28 [95% CI:1.38-20.25], p=0.015), white blood cell counts (HR=1.09 [95% CI:1.02-1.18], p=0.014), and hemoglobin (Hb, HR=0.97 [95% CI:0.95-0.99], p=0.006) were independently risk factors for survival. We created a nomogram as well as a web portal that enables survival predictions based on individualized parameters ( https://cae29l-jia-chen.shinyapps.io/DynNomapp/ ). The C Index of the nomogram was 0.818. The AUC of 3-year, 5-year, and 10-year survival of the nomogram were 0.854, 0.769, and 0.813, respectively. Sex biases were observed at Hb levels that contribute outcome heterogeneity in such ET patients. Conclusions : We provided a new dynamic nomogram that can well evaluate the survival prognostication for a given ET patient with a previous history of thrombosis, with a good discrimination and excellent performance.

Do Hematologic Parameters Predict Thrombosis or Disease Transformation in Essential Thrombocythemia?

Background: Patients with essential thrombocythemia (ET) are burdened with an increased risk of thrombosis and disease transformation, both significant contributors to morbidity and mortality. However, based on the available literature, there are limited tools available to predict the development of these complications. Particularly, the association between hematologic parameters and thrombosis is unclear, making risk stratification and disease management challenging. Utilizing a large retrospective database, we assessed the impact of hematocrit (Hct), red blood cell count (RBC), white blood cell count (WBC), and platelet count (Plt) on the subsequent development of thrombosis and disease transformation to myelofibrosis (MF), polycythemia vera (PV), and acute leukemia. Methods: We included ET patients treated at our institution between 2007 and 2021. The index time was date of diagnosis or date of first contact at Mount Sinai Hospital for patients with a prior history of ET. Hematologic parameters (Hct, RBC, WBC, Plt) were documented at three-month intervals after the index time. Patients were included in the study if they had at least three sets of laboratory values prior to the outcome of interest. For each hematologic parameter, we performed univariate cox analysis of time to thrombosis or progression to either MF, PV, or acute leukemia. Each lab parameter was analyzed as a time dependent covariate, taking into account the length of time the patient was above or below the threshold of interest. Hct and plt were specifically evaluated as dichotomous variables, with a cut off of less than or greater than 45% for Hct based on CYTO-PV results. For plt, two cut-off values were used: less than or greater than 400 (based on ELN response criteria) and less than or greater than 600 (based on Cortelazzo et al HU treatment goal) in plt/microliter. Results: We identified 430 patients who met criteria and were included in the analysis. Our cohort of patients was mostly female (61%), non-Hispanic (66%), white (64%), JAK2 mutated (60%), with an average age at diagnosis of 56 years and a median follow-up time of 33 months. 41 (7%) patients had a history of prior thrombosis. There was a total of 23 major thromboses that occurred after the index time with 12 venous and 11 arterial thrombotic events. 38 patients progressed to post ET-MF, 20 patients developed post ET-PV, and 10 patients transformed to acute leukemia. For the assessment of thrombotic risk, there were no significant associations between any of the hematologic parameters and this outcome. We also evaluated the risk of thrombosis in the JAK2 positive subset of patients (n of 15), and did not find any significant association with any of the lab parameters (in particular, for hct < 45%, p > 0.99). For transformation to MF, plt < 400 x10 9/L was associated with an increased risk of the development of post-ET MF (HR 2.2, p 0.016), and the same was seen with plt < 600 x10 9/L (HR 2.2, p 0.044). The development of PV was less likely with a hct lower than 45% (HR 0.03, p < 0.001), with similar results seen for plt < 400 x10 9/L (HR 0.2, p 0.03) and plt < 600 x10 9/L (HR 0.2, p 0.002). For transformation to acute leukemia, plt < 400 x10 9/L (HR 8.3, p 0.008) was associated with an increased risk of this complication. Conclusions: In this retrospective cohort of 430 patients with ET, we found no associations between four different hematologic parameters over time with thromboses. In particular, this data once again argues against aiming to achieve a particular platelet goal to minimize thrombosis in ET patients. The lack of association between hematologic parameters and thrombotic risk was similarly exemplified in our subset of JAK2 mutated ET patients. Pertaining to disease transformation, plt count appeared to be the most predictive out of all of the parameters, with lower plt values corresponding to increased risk of both post-ET MF and acute leukemia, which both warrant further exploration. A hct level of less than 45% appeared to be protective against the development of post-ET PV. Significant limitations of our study include the retrospective nature as well as the small number of events of interest that our patients experienced. Future studies must continue to focus on surrogate endpoint validation in order to more reliably predict thrombotic events as well as disease progression in patients with ET given the significant morbidity and mortality that such events incur.

Real-World Experience of Ropeginterferon-Alfa Treatment of PV and ET - Two Centers Experience

BACKGROUND AND AIM: Interferon alpha is an effective treatment for Polycythemia Vera (PV) and Essential Thrombocythemia (ET) and is the only treatment known to induce sustained molecular responses by decreasing JAK2 mutation allelic burden. Long-acting pegylated interferons are better tolerated. Ropeginterferon-alfa is a monopegylated interferon with a longer half-life and is the first interferon to be FDA-approved for the treatment of PV. It is not yet approved for ET, but clinical trials are ongoing. Given the similar disease biology between PV and ET and the efficacy of pegylated interferon-alfa in both PV and ET, this study aims to look at a real-world experience of treating PV and ET with ropeginterferon-alfa since its approval. METHODS: We conducted a retrospective chart review of all our PV and ET patients treated with ropeginterferon-alfa at Huntsman Cancer Institute, University of Utah (SLC cohort), and at the University of North Carolina at Chapel Hill (UNC cohort), since the drug's approval for PV from November 2021 through June 2023. The complete hematologic response (CHR) was defined as the normalization of blood counts within the reference range of the local lab standards. Prior to ropeginterferon-alfa, the participants were managed with therapeutic phlebotomies, or cytoreduced with either hydroxyurea, pegylated interferon-alpha 2a ( Pegasys), JAK2 inhibitors, or were newly diagnosed and previously untreated. RESULTS: A total of 120 patients (76 in SLC cohort and 44 in UNC cohort) were included in this study. Of those, 75 (62.5%) were diagnosed with PV, 37 (31%) with ET, and 1 with congenital polycythemia due to germline JAK2 mutation. Twenty-three (19%) patients had a prior history of thrombosis. JAK2 mutation was present in 100 (83%) patients, while 9 (7.5%) were CALR mutated, 1 with MPL mutation, and 1 with triple-negative ET. Extended myeloid gene panel sequencing was available in 64 (53.3%) patients and 35 of them (54.6%) patients had additional somatic mutations. Most common somatic mutations include TET2 (11 patients) and DNMT3A (8 patients) and CBL (3 patients), among others. Of the cohort, 15 (12%) patients discontinued ropeginterferon-alfa due to various adverse events, which included: fatigue, joint aches, skin rash, and increased anxiety and depression. Of the 105 patients who are on ropeginterferon-alfa, 9 patients were previously untreated patients while 96 (91.4%) were pretreated with other therapies and switched to ropeginterferon-alfa. In many patients, the switch to ropeginterferon-alfa was done because of the increased frequency and aggressivity of squamous cell skin cancers while on hydroxyurea treatment. All of them started ropeginterferon-alfa at a dose of either 50 mcg or 100 mcg every two weeks and were increased at an increment of 50 mcg to achieve a goal of CHR. As most of the patients were switching from prior therapies, 51 (49%) were already in CHR at the time of initiating ropeginterferon-alfa. The median ropeginterferon-alfa dose to maintain CHR was 50mcg in the SLC cohort and 100mcg in the UNC cohort. (See table for more details). We have 6 patients with DNMT3A mutation, 4 (66.6%) have achieved CHR at a median ropeginterferon-alfa dose of 100 mcg (range 50 mcg - 150 mcg), and 2 patients are undergoing dose titration. Of the 11 patients with TET2 mutation, 7 (63.3%) achieved CHR at a median ropeginterferon-alfa dose of 150 mcg (range 50 mcg - 500 mcg). The analysis of JAK2 V617F and CALR allelic burden, transcripts of inflammatory, prothrombotic, and hypoxia-regulated (HIFs) genes, and evaluation of females for reversal of clonal to polyclonal myelopoiesis is ongoing. CONCLUSION: Ropeginterferon-alfa is effective in PV and ET, however, the dose that achieves CHR is highly individualized, necessitating an incremental titration approach. The patients already in CHR from prior therapy needed relatively lower doses of ropeginterferon-alfa to maintain CHR. Clinical trials are ongoing with an alternate accelerated dosing scheme and results are awaited.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

P1692: PREDICTIVE MODEL FOR VEIN THROMBOEMBOLIC EVENTS DEVELOPMENT IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Background: Patients with acute myeloid leukemia (AML) are at increased risk of vein thromboembolic events (VTE). However, thromboprophylaxis is largely underused, mainly due to increased risk of bleeding and limited number of studies analizing risk factors for VTE development. Aims: To assess potential risk factors for the VTE development and develop a simple predictive model, based on patients and disease-related parameters. Methods: We conducted a retrospective cohort study of adult patients with newly diagnosed AML who were treated in our institution between January 2009 and December 2021. Patients with AML-M3 were excluded. Primary end point of our study was imaging-confirmed VTE including simptomatic central venous catheter -related thrombosis (CVC). Participants were followed from the AML diagnosis to death or 6 months after the last cycle of therapy. We analyzed demographic factors (age, gender), Eastern Cooperative Oncology Group performance status (ECOG PS), body mass index (BMI), smoking status, comorbidities, Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), baseline laboratory findings (complete bood counts, fibrinogen, PT, PTT, D dimer, LDH) leukemia related paremeters (cytogenetics, molecular genetics (FLT3, NPM), flow cytometry), Khorana score (KRS) as potential risk factors for the VTE development. Univariate and multivariate logistic regression model was used as the method for analyzing binary outcome (VTE development) and potential predictors. Based on our final model we cretaed a nomogram to enable calculalation of probability of VTE development. Results: The study population included 608 eligible AML patients, mean age 55 (range: 18-81) years, male/female 341/267 (56.1%/43.9%). During the follow-up period 81/608 (13.3%) patients developed VTE: CVL 61/608 (10.0%), deep vein thrombosis 16/608 (2.63%), pulmonary embolism 4/608 (0.01%). Before therapy, during induction, consolidation, transplantation and relapse VTE were developed in 5/81 (6.2%), 36/81 (44.4%), 30/81 (37%), 4/81 (4.9%), 6/81 (7.4%) patients respectively. Among all tested parameters five which are independent predictictors were included in predictive model: male sex (p=0.020, OR 1,92 95% CI: 1.11-3.31), prior history of TE (p=0.001, OR 3.83, 95% CI: 1.72-8.55), PT (p=0.107, OR 1.01, 95% CI: 0.99-1.03), ECOG PS (p=0.038, OR 0.72, 95% CI: 0.53-0.98), HCT-CI (p=0.032, OR 0.79, 95% CI: 0.64-0.98). All other patient and disease related paremeters, including Khorana score were not predictive. Our nomogram provides a visual depiction of the relative contribution of each prognostic factor to the total point score and, thus, the weight of factors regarding probability for VTE development (Picture 1). Image:Summary/Conclusion: Our study point out that: 1. A KRS score has no predictive value in AML; 2. Male patients and patients with history of prior thrombosis have 1.92 and 3.83 higher odds of developed VTE; 3. Increasing of ECOG and HCT-CI for one point decrease probability of develope thrombosis for 28% and 21%; 4. Thromboprophylaxis should be considered in patients with prior history of TE, especially with male sex, good PS and low HCT-CI. Our nomogram may help clinicians in clinical decision making. However, validation of our predictive model through prospective study with a larger number of patients are required.

European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.

European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.

Prior History of Thrombosis, Meld, BMI and the Presence of Esophageal Varices Predict Thrombus Progression in Patients with Untreated Splanchnic Vein Thrombosis

Background: Splanchnic vein thrombosis (SVT) occurs in a heterogenous group of patients secondary to a variety of risk factors including acute and chronic liver disease, malignancy, and myeloproliferative neoplasms. There is equipoise on the utility of anticoagulation in many patients with SVT given the perceived risks of bleeding and unclear benefits. We sought to determine which clinical factors predict new or progressive thrombosis in a cohort of patients with SVT.Methods: We undertook a retrospective cohort study of patients over 18 years of age identified to have an SVT at the Oregon Health & Science University from 01/01/2015 - 12/31/2020, including only patients who were not initially treated with anticoagulation at the time of their initial VTE diagnosis. Relevant clinical variables were selected apriori. The primary study endpoint was imaging-confirmed progression of SVT, development of cavernous transformation, intestinal ischemia, or new venous or arterial thrombosis. Chart demographics, patient history, and relevant lab values at the time of initial SVT were extracted for the analysis. Descriptive analysis, univariate logistic regression, and multivariable logistic regression were performed in STATA version 12.1 and R (R core team 2019).Results: Seventy-eight patients were included in the analysis (mean age 60 years old, 74% male). The most common SVT in the cohort was isolated portal vein thrombosis (N=60) followed by thrombosis of multiple splanchnic veins (N=14). The most prevalent causes of liver disease in the cohort were viral hepatitis (N=33) alcoholic cirrhosis (N=20) and non-alcoholic steatohepatitis (N=12). 66% of patients had known varices at diagnosis. 33% had thrombosis directly associated with a tumor. The mean platelet count and INR were 105 x 109/L and 1.55 respectively. Twenty-two patients (28%) developed the primary endpoint of thrombus progression. Univariate logistic regression found that prior history of thrombosis (OR 6, P= 0.04) and the presence of varices at diagnosis (OR 4.4, P= 0.02) were associated with progression. We then created a multivariable logistic regression model and observed that total bilirubin (ORadj = 0.34, p = 0.03), MELD score (ORadj = 1.33, p = 0.04), the presence of varices (ORadj = 11.7, 0.03), and BMI (ORadj = 1.14, p = 0.047) were significant predictors of our composite outcome while controlling for age, glomerular filtration rate, INR, and prior history of VTE.Discussion: In our heterogenous cohort of patients with SVT not treated with anticoagulation, one in four patients developed the composite endpoint of SVT progression, development of cavernous transformation, intestinal ischemia, or new venous or arterial thrombosis. Several common clinical variables appear to be predictive for thrombus progression, suggesting that predictive models may be feasible to determine which patients with SVT are likely to benefit from anticoagulation. DisclosuresShatzel: Aronora Inc,: Consultancy.

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

European Leukemianet (ELN) Response Predicts Disease Progression but Not Thrombosis or Death in Polycythemia Vera (PV): An Analysis of a Multicenter Database

Renal Function and Risk of Arterial Thrombotic Events in Patients Positive for Lupus Anticoagulant

Background: Patients with lupus anticoagulant (LA) are at risk for arterial and venous thromboembolic events. Recent work suggests that LA positive patients who experience thrombotic events in different vascular beds constitute distinct subgroups. To risk stratify patients, further work is needed to better characterize predictors for thromboembolic events in these subgroups.Aims: The aim of this study was to identify baseline characteristics and laboratory parameters associated with the development of arterial or venous thrombotic events.Methods: Patients with at least 2 previous positive LA tests were serially monitored for thrombotic events within the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Patients without clinical follow-up were excluded from this analysis. Statistical analysis was performed with RStudio (Version 1.1.442).Results: One-hundred-eighty-seven patients were followed (Table 1) for a median of 11.4 years and 1865 follow-up visits (median visit/patient=9). Fifty-seven prospective thrombotic events (TE), including 27 arterial thrombotic events (ATE) and 30 venous thrombotic events (VTE), were observed. This corresponded to 10-year prospective ATE, VTE and overall thrombosis incidences of 13.9% [95%CI: 8.3, 19.6], 18.8% [12.2, 25.4], and 32.0% [24.1, 39.8], respectively. (Figure 1). Thirty-seven of the 57 events occurred in patients with a prior history of thrombosis (“recurrent thrombosis”).In univariable competing risk analysis, age (subdistribution hazard ratio (SHR) = 1.02, 95% CI: 1.00-1.05, p=0.019), body mass index (BMI, 1.05, 1.00-1.11, p=0.042), history of ATE (3.14, 1.45-6.81, p=0.0038), active smoking (2.16, 1.00-4.62, p=0.049), diabetes (4.16, 1.47-11.8, p=0.0073), VKA use at baseline (0.42, 0.18-0.97, p=0.042), aCL IgM positivity (2.48, 1.05-5.83, p=0.038), aβ 2GPI IgM positivity (2.86, 1.18-6.93, p=0.020), mean platelet volume (1.17, 1.06- 1.30, p=0.0024), creatinine (3.76, 1.32- 10.7, p=0.013), and estimate glomerular filtration rate (eGFR, 0.98, 0.96-0.99, p=0.0011) were associated with prospective risk of ATE (Table 2). Conversely, the prospective risk of VTE was univariably associated only with prior history of VTE (3.26, 1.40-7.68, p=0.0061).After adjusting for traditional arterial thrombotic risk factors (age, sex, BMI, active smoking, diabetes,), history of ATE (SHR = 3.97, 95% CI: 1.71-9.025, p=0.0014), prior history of both ATE and VTE (3.87, 1.06-14.16, p=0.041), creatinine (3.93, 1.22-12.66, p=0.022), and eGFR (CKD-EPI, 0.96, 0.96-0.99, p=0.0037) remained independently associated with prospective risk of ATE (Table 2).In detail, the 10-year cumulative risk of ATE was 24.9% [95%CI: 8.8, 41.0], 15.0% [5.8, 24.2], and 6.7% [2.2, 13.8] in patients with a baseline eGFR less than 60 mL/min/1.73m 2, between 60 and 89 mL/min/1.73m 2, and greater than or equal to 90 mL/min/1.73m 2, respectively (Gray's test, p=0.019, Figure 2).Conclusion: Approximately 14% of patients persistently positive for LA experienced an ATE over 10 years. After adjusting for traditional arterial risk factors, decreased renal function was associated with an increased prospective risk of ATE. Notably, decreased renal function was not associated with development of VTE and the association with ATE was also independent of underlying SLE, LLD, or rheumatic disease (data not shown). Clinically, LA positive patients with decreased renal function may represent a subgroup that might benefit from more aggressive anti-thrombotic therapy or anti-thrombotic prophylaxis. [Display omitted] DisclosuresPabinger: Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NovoNordisk: Consultancy, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding.

Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients

Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5–9.5%) and 12.3% (6.4–18.2%) respectively. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1–3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.

Management Issues and Controversies in Low-Risk Patients with Essential Thrombocythemia and Polycythemia Vera.

Essential thrombocythemia (ET) and polycythemia vera (PV) are the most common myeloproliferative neoplasms (MPNs). Treatment of ET and PV is based on the risk for subsequent thrombosis. High-risk patients, defined as older than 60, JAK2 V617F-positive patients, or patients with a history of prior thrombosis, merit cytoreduction to control blood counts, whereas a watchful waiting paradigm is utilized in low-risk patients. However, low-risk patients have a host of other specific management issues that arise during their disease course. This review will discuss the most common management issues specific to the care of low-risk patients, including anti-platelet therapy dosing, pregnancy, and indications for early cytoreduction. Although low-dose aspirin is well established in PV, its indications and dosing regimens are less clear in ET. Recent evidence has supported twice daily low-dose aspirin in ET and observation alone in very low-risk ET patients. Pregnancy is not contraindicated in MPNs, and we recommend aspirin throughout pregnancy with consideration for prophylactic postpartum anticoagulation. High phlebotomy needs, symptom burden, and extreme thrombocytosis are common reasons for initiation of cytoreduction in low-risk patients, although we typically do not start cytoreduction for an isolated high platelet count alone. Recent data has also demonstrated a potential disease-modifying effect of interferons in MPNs, with some experts now advocating the early use of interferon in low-risk patients, although more mature data is needed before practice guidelines change. We evaluate the literature to inform clinical decision-making regarding these controversies, including most recent data that has challenged the "watchful waiting" paradigm. Our discussion provides guidance on common clinical scenarios seen in low-risk ET and PV patients, who face a myriad of complex management decisions in their care.

Study Of Chronic Atrophic Gastritis In Patients With Autoimmune Thyroid Disease

ABSTRACT Background: Patients with autoimmune thyroid disease (ATD) may have a greater frequency of anti-parietal cell antibodies (APCA) than the general population. Aim of the study: The study's goal is to look at chronic atrophic gastritis in people who have autoimmune thyroid illness. Patients and Methods: In 60 ATD patients, APCA was detected using an indirect immunofluorescence test: 33(55%) had Graves' disease and 27(45%) had Hashimoto's thyroiditis. A systematic questionnaire was used to assess gastrointestinal symptoms, prior history of thrombosis, arthralgia, and other autoimmune disorders in patients and their families. Individuals with both positive and negative APCA were compared. Patients who tested positive were encouraged to have upper gastrointestinal endoscopy and numerous biopsies of the antral, body angular, and prepyloric segments performed. As controls, sera from 30 healthy people hailing from the same geographic region were utilized. Results: APCA was found in 20% (12/60) of ATD patients, including 21.3 percent (7/33) in the Graves' group and 18.6 percent (5/27) in the Hashimoto's sample (P = 0.796). Positive APCA patients exhibited greater anemia (P > 0.001) and reduced heartburn and epigastric discomfort (P = 0.002&0.004, respectively). A total of 66.7 percent of the 12 APCA-positive patients who underwent upper endoscopy exhibited chronic atrophic gastritis. Conclusion: ATD patients have a significant prevalence of positive APCA. APCA are more frequent in people who have anemia and much less in those suffering heartburn or epigastric discomfort. Approximately 66.7 percent of APCA-positive individuals had chronic atrophic gastritis.

Polycythemia Vera (PV): Update on Emerging Treatment Options.

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by exuberant red cell production leading to a broad range of symptoms that compromise quality of life and productivity of patients. PV reduces survival expectation, primarily due to thrombotic events, transformation to blast phase and post-PV myelofibrosis or to development of second cancers, which are associates with poor prognosis. Current therapeutic first line recommendations based on risk adapted classification divided patients into two groups, according to age (< or >60 years) and presence of prior thrombotic events. Low-risk patients (age <60 years and no prior history of thrombosis) should be treated with aspirin (81–100 mg/d) and phlebotomy, to maintain hematocrit <45%. High-risk patients (age >60 years and/or prior history of thrombosis), in addition to aspirin and phlebotomies, should receive cytoreductive therapy in order to reduce thrombotic risk. Nowadays hydroxyurea still remains the cytoreductive agent of first choice, reserving Interferon to young patients or childbearing women. During the last years, ruxolitinib emerged as a new treatment in PV patients, as second line therapy: it appeared especially effective in patients with severe pruritus, symptomatic splenomegaly, or post-PV myelofibrosis symptoms. Currently, in PV treatment, several molecules have been tested or are under investigation. At present, the drug that has shown the most encouraging results is givinostat.

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=&amp;lt;0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Thrombosis Risk in Transgender Adolescents Receiving Gender-Affirming Hormone Therapy

An estimated 2-3% of US youth identify as transgender or gender non-conforming (hereafter transgender). Transgender youth may suffer from gender dysphoria, a condition associated with many health risks, including high risk of suicide. Transgender individuals have a 40% greater risk of attempting suicide than cis-gender individuals. Gender-affirming hormone therapy (GAHT) is associated with improvement of gender dysphoria and amelioration of the risk of suicide. GAHT consists of either estrogen [for transgender women (TGW)] or testosterone [for transgender men (TGM)]. However, GAHT may be associated with other risks, most notably thrombosis. Numerous studies documented increased thrombosis risk in cis-gender women using exogenous estrogen for contraception or hormone replacement therapy. Studies of GAHT suggest a risk of thrombosis with estrogen use; however, this data is not uniform. Studies of testosterone replacement in cis-gender show conflicting results with respect to thrombosis risk. All previous studies examining the risk of thrombosis with GAHT have included adults exclusively. Therefore we sought to determine the risk of thrombosis in a cohort of transgender youth receiving standardized GAHT regimens. Transgender youth have potential for a much longer exposure to GAHT, thus having different life-time risk of thrombosis than patients that start GAHT at an older age. Of all 1406 patients seen at the Cincinnati Children's Medical Center Transgender Health Clinic since its inception, 611 subjects started GAHT and were eligible for inclusion in the cohort. Of these, 176 (28.8%) identified as female, 416 (68.1%) as male, and 19 (3.1%) as non-binary. Thrombosis risks were common among the cohort: 34.5% had obesity, 15.4% used tobacco, 4.6% had migraine with aura, and 8.0% had a family history of thrombosis. Three subjects had a prior history of thrombosis: 2 with venous thromboembolism (VTE) and one with a stroke. 53.7% of the cohort had previously used hormones, most commonly for menstrual suppression. Of those with prior hormone use, the vast majority had used progesterone-only methods (5.7% previously used estrogen-containing contraceptives). All patients initiating GAHT were treated according to current guidelines with monitoring of estrogen and testosterone levels and titration of GAHT doses accordingly. Overall, 29.8% initiated estrogen therapy and 70.2% started testosterone therapy. Among the cohort, 17 individuals were referred to Hematology for evaluation for thrombosis risk prior to starting GAHT. The most common laboratory abnormality for these individuals was elevated factor VIII, elevated plasminogen-activator inhibitor 1 (PAI-1), and the PAI-1 polymorphism. Two TGW and one TGM started thromboprophylaxis prior to initiating GAHT due to thrombotic risk factors. Despite the presence of preexisting risk factors, no individual in the cohort developed a thrombosis (VTE or stroke) during GAHT. This is the first study to examine thrombosis risk of GAHT in an exclusively adolescent and young adult population. While there were no incidents of thrombosis in our cohort, we found individuals at risk for thrombosis. Careful history and counseling regarding risks are needed when discussing initiation of GAHT for transgender individuals. Additionally, further studies looking at long-term risk are needed. Disclosures Mullins: Takeda, Bayer: Other: Advisory Board.

Thromboprophylaxis in the End-of-Life Cancer Care: The Update.

Cancer patients are at increased risk for venous thromboembolism (VTE), which further increases with advanced stages of malignancy, prolonged immobilization, or prior history of thrombosis. To reduce VTE-related mortality, many official guidelines encourage the use of thromboprophylaxis (TPX) in cancer patients in certain situations, e.g., during chemotherapy or in the perioperative period. TPX in the end-of-life care, however, remains controversial. Most recommendations on VTE prophylaxis in cancer patients are based on the outcomes of clinical trials that excluded patients under palliative or hospice care. This translates to the paucity of official guidelines on TPX dedicated to this group of patients. The problem should not be underestimated as VTE is known to be associated with symptoms adversely impacting the quality of life (QoL), i.e., limb or chest pain, dyspnea, hemoptysis. In end-of-life care, where the assurance of the best possible QoL should be the highest priority, VTE prophylaxis may eliminate the symptom burden related to thrombosis. However, large randomized studies determining the benefits and risks profiles of TPX in patients nearing the end of life are lacking. This review summarized available data on TPX in this population, analyzed potential tools for VTE risk prediction in the view of this group of patients, and summarized the most current recommendations on TPX pertaining to terminal care.

Profile of Myeloproliferative Neoplasms in Kuwait: Population-Based Study

Introduction Myeloproliferative neoplasms (MPNs) are a group of hematopoietic disorders of stem-cell origin, characterized by mutations that disrupt hematopoietic signal-transduction pathways. The Middle East lacks an MPN registry representative of the disease in our area. Here we report on the epidemiology of these neoplasms in our area, including phenotype, clinical features and relevant outcomes. Methods This population-based study reports various demographic characteristics and clinical attributes of all suspected and confirmed MPN patients from all over Kuwait referred to the research hematology lab at Kuwait University &amp; cytogenetic lab in Kuwait Cancer Control Centre (KCCC) during the period from 2007 to 2018. Molecular determination of the patients' driver mutation status currently relies on ARMS-PCR. Confirming a diagnosis follows the WHO criteria, and its refinements, for the diagnosis of MPNs. Data entry and analysis was performed using SPSS (v.22) software. Results Most patients are ≥ 40 years old (79.8%), with a median age of 55 years. Gender distribution is almost equal, with ethnic categorization as Kuwaiti and Non-Kuwaiti showing a similar pattern. ET is the most common diagnosis (40.1%), followed by PRV (32.3%). JAK2 V617F mutation is reported positive in 89.7% of cases, followed by CALR in 8.0% of MPNs. The incidence of MPNs ranged from 0.5 to 2.1 per 100,000 in 2007 through 2018. The lowest rate was recorded in 2007 (0.511) and the highest was observed in 2011 and 2016 (2.417 and 2.101, respectively). The increase in 2011 is likely due to the introduction of a more sensitive technique using ARMS-PCR for the diagnosis of MPNs, whereas the increase in 2017 may be explained by the publication of WHO 2016 modified criteria. Moreover, throughout the years, the distribution of MPNs in different age groups showed similar pattern, with the highest incidence in patients aged ≥ 60. Driver mutations can fit with a general increase in incidence from 2007-2017, which may be attributed to increased awareness among treating physicians asking suspected cases to screen for MPNs using molecular techniques.One hundred and twenty-four (18.5%) cases were documented to have a prior history of thrombosis, with roughly equal distribution between arterial and venous sites. A large proportion (89.5%) of the thrombotic events occurred in those who are ≥ 40 years old, with most events being associated with ET (34.7%) and PRV (33.1%). Almost one-third of cases of thrombosis were associated with undetermined MPN diagnosis. Participating patients were categorized as either low or high risk for thrombotic events, with the latter being defined as age ≥ 55 years and the presence of a previous thrombotic event. The results demonstrate that a total of 46 cases were defined as high risk, most of them being associated with ET (20 cases) and PRV (19 cases). A statistically significant association was reported between gender and site of occurrence of thrombotic events, with males having more arterial thromboses, and females were documented to have more venous thromboses. Conclusion JAK2 V617F driver mutation is the most common positive finding in the participating patients. Roughly one-fifth of the participants encountered thrombotic events, and the site of thrombosis is associated with gender, demonstrating statistical significance. These results should warrant a more thorough evaluation of MPNs in Kuwait to provide a better understanding of its epidemiology. This can be achieved through optimized documentation of patients' data, and testing for additional novel driver mutations and transformation; as well as encourage physicians in primary care centers to refer suspected cases for molecular diagnosis. Disclosures No relevant conflicts of interest to declare.

PB1857 THE ROLE OF WHOLE‐BODY MAGNETIC RESONANCE IMAGING IN THE DETECTION OF VASCULAR EVENTS IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA.

Background:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by intravascular hemolysis, cytopenias, and recurrent thrombosis. Thrombotic events are just the main cause of morbidity and mortality. Therefore, it is essential to detect them early to treat them and avoid sequels.Aims:To analyze the diagnostic value of the whole‐body magnetic resonance imaging (WB‐MRI) in the detection of symptomatic and silent vascular events.Methods:Retrospective study in which a 1.5 Tesla whole‐body magnetic resonance (Philips Achieva, Philips Medical Systems, Best, the Netherlands) with Gadolinium contrast was performed along 2017 and 2018 to patients diagnosed of classical PNH in Autonomous Community of the Region of Murcia, Spain. The image findings were analyzed.Four patients were included (3 men and 1 woman) with median age of 54 years, diagnosed of either PNH (n = 2) and AA/PNH (n = 2). At the time of investigation, mean size clon in granulocytes measured by FLAER was high (90.7 %, range 75.6‐99.3 %) and mean LDH was 341.7 U/L (range 204‐465 U/L; normal range 135‐214 U/L). Only one patient had prior history of thrombosis (Budd‐Chiari syndrome). All patients were treated according to Spanish PNH guidelines, including the use of complement inhibitor Eculizumab.Results:WB‐MRI findings showed unknown bone infarctions in two (50%) patients (patient 1 and patient 3). In patient 1, symptomatic bone infarctions was diagnosed (both femoral condyle and proximal tibias). Patient 3 showed an asymptomatic area of bone edema in distal left radial bone.Summary/Conclusion:Although the sample from our study is very small, it seems that WB‐MRI could be useful to evaluate vascular events, like bone infarctions, even subclinical ones. Our findings are consistent with the only article published to date (Alaskar et al. Sci Rep. 2018; 8: 13458). Further studies are needed to test the effectiveness of WB‐MRI in the detection of vascular events and their relationship as a thrombotic event in PNH.imageimage

Management and Outcome of 11 Pregnancies in Women with Polycythemia Vera

Background: Unlike to Essential Thrombocythemia, Polycythemia Vera (PV) is rare in women of childbearing age, with only few previous pregnancies reported in literature; a positive outcome of pregnancy has been described in about 2/3 of cases and maternal complications in about 1/4 of delivery.Aims and Methods: We retrospectively analyzed outcome and complications in a series of 11 pregnancies in 7 females with PV. These patients were diagnosed and managed between 2000 and 2017 in 3 Italian Centers. PV diagnosis was perfomed or revised according to WHO 2016 criteria. Different therapeutic approaches have been assessed prior and during each pregnancy.Results: Median age at diagnosis and at conception were 24.3 and 30.1 years, respectively. According to molecular status, all patients presented JAK2V617F mutations. Four patients (57.1%) had two pregnancies. All patients received phlebotomies as required, with a median hematocrit (Ht) level at the time of conception of 45.2% (range: 41.4-46.8). Median values of WBC and PLT at conception were 9.9 x 109/l (range: 6.7-18.3) and 510 x 109/l (250-917). Only one patient presented a history of thrombosis (2 TIA) occurred before first pregnancy. Three (42.8%) females presented cardiovascular risk factors at the time of conception, while a thrombophilic predisposition was documented in 3 patients (42.8%).Among the 11 pregnancies, 8 (72.7%) ended with a full term delivery, while 2 (18.2%) were complicated by a fetal loss in the first trimester and by an Intrauterine growth retardation with preterm delivery. It is worth of note that the fetal loss was reported in the patient with prior arterial thrombosis and concomitant signs of myeloproliferation (mild leukocytosis, Ht level > 45% and PLT level > 900 x 109/l), while the intrauterine growth retardation was reported in a patient with Ht level > 45%, despite the typical hemodiluition of pregnancy. The remaining pregnancy was characterized by maternal complications, consisting of an extra-tubal pregnancy with consequent laparoscopic surgery approach and fetal death. The global live birth rate was 81.8 %.Anti-thrombotic treatment was administered in all but one pregnancy, consisting of low-dose acetil salicylic acid (ASA) already started since PV diagnosis and continued during pregnancy in 6 pregnancies (54.5%), or a combination of ASA and Low Molecular Weight Heparin (LMWH) during the second and last trimester of pregnancy and post-partum in the remaining 4 pregnancies (36.3%). Two patients were also treated with interferon-alfa during their pregnancy. One patient was receiving hydroxyurea at the time of conception, which was immediately stopped.Conclusions: Our data indicate that PV patients may develop pregnancy complications in about 1/4 of cases (27.2%), but the risk of fetal loss (18.2%) is lower than recently reported in similar series of PV females. The vast majority of our patients received ASA +/- LMWH during pregnancy and post-partum, suggesting an important role of anti-thrombotic treatment in reducing incidence of fetal complications. The history of prior thrombosis and the signs of myeloproliferation at conception and at delivery seem to be associated to development of fetal complications. Considering the current guidelines for the management of PV, in particular the more aggressive control of Ht (with Ht target < 45%), it is possible that the large application of this approach also in PV pregnancies could further improve the rate of fetal complications. Larger collaborative multicenter studies, in order to better clarify the optimal management of pregnancy in PV, are warranted. DisclosuresBreccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.